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A New Fungal Diterpene Induces VDAC1-dependent Apoptosis in Bax/Bak-deficient Cells
Authors:Li Huang  Junjie Han  Danya Ben-Hail  Luwei He  Baowei Li  Ziheng Chen  Yueying Wang  Yanlei Yang  Lei Liu  Yushan Zhu  Varda Shoshan-Barmatz  Hongwei Liu  Quan Chen
Abstract:The pro-apoptotic Bax and Bak proteins are considered central to apoptosis, yet apoptosis occurs in their absence. Here, we asked whether the mitochondrial protein VDAC1 mediates apoptosis independently of Bax/Bak. Upon screening a fungal secondary metabolite library for compounds inducing apoptosis in Bax/Bak-deficient mouse embryonic fibroblasts, we identified cyathin-R, a new cyathane diterpenoid compound able to activate apoptosis in the absence of Bax/Bak via promotion of the VDAC1 oligomerization that mediates cytochrome c release. Diphenylamine-2-carboxilic acid, an inhibitor of VDAC1 conductance and oligomerization, inhibited cyathin-R-induced VDAC1 oligomerization and apoptosis. Similarly, Bcl-2 overexpression conferred resistance to cyathin-R-induced apoptosis and VDAC1 oligomerization. Silencing of VDAC1 expression prevented cyathin-R-induced apoptosis. Finally, cyathin-R effectively attenuated tumor growth and induced apoptosis in Bax/Bak-deficient cells implanted into a xenograft mouse model. Hence, this study identified a new compound promoting VDAC1-dependent apoptosis as a potential therapeutic option for cancerous cells lacking or presenting inactivated Bax/Bak.
Keywords:B-cell lymphoma 2 (Bcl-2)  Bax  mitochondrial apoptosis  protein cross-linking  voltage-dependent anion channel (VDAC)  Bcl2  cyathane diterpenoid  oligomerization
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